All but one study administered both of the ICS+LABA combinations in a single inhaler; one trial administered BUD+FM in separate 101 101 95 inhalers buy kamagra chewable 100mg with amex. Study duration ranged from 12 weeks to seven months buy generic kamagra chewable 100 mg. All four trials administered BUD and FM via DPI; three did so in a single DPI; one trial administered 101 BUD+FM in separate inhalers. All four trials administered the same total daily dose of FP/SM (500/100), which is considered a medium daily dose of ICS when delivered via DPI and a high daily dose when delivered via pMDI (Table 3). In two trials, 95-97 500mcg of FP was compared with an equipotent daily dose of BUD. In one of these, there was a third arm that contained an adjustable-dose BUD/FM arm, although this is not a comparison of interest for the current report. Of the non-equipotent dosage studies, one study compared low (but adjustable) and medium (but fixed) daily doses of BUD with a high dose of 98-100 101 FP, and another compared a high daily dose of BUD with a medium dose of FP. Study Populations The four head-to-head RCTs included a total of 5,818 subjects. All studies were conducted in adolescent and/or adult populations. All enrolled subjects that were not adequately controlled on current therapy. Three were conducted in subjects with moderate to severe persistent asthma; one did not report the 98, 99 severity classification. Three trials (75%) excluded smokers with at least a 10 pack-year history; one (25%) allowed some smokers and reported that 5% to 7% of subjects in each group were current smokers. Sponsorship Of the four head-to-head trials, 3 (75%) were funded by pharmaceutical companies; 1 trial (25%) did not report the source of funding but at least one author had a primary affiliation with a pharmaceutical company. No trials were funded primarily by a source other than a pharmaceutical company. Controller medications for asthma 63 of 369 Final Update 1 Report Drug Effectiveness Review Project Head-to-head comparisons 1. Budesonide/formoterol (BUD/FM) compared with Fluticasone/salmeterol (FP/SM) All four trials and the systematic review reported asthma symptoms and exacerbations (Evidence Tables A and B). Symptoms reported by at least two of the trials were weeks with “well- 95-97 97-100 95- controlled” asthma, symptom-free days, , nocturnal awakenings / symptom-free nights, 101 98-100 95-97 , and asthma symptoms scores – as either total or daytime scores. In addition, one trial 101 98- reported nights with a symptom score <2, and another reported ACQ and AQLQ(S) scores. Number of missed days of work 98-100 and AQLQ(S) score were reported by one study, Finally, one study reported rates of non- emergency health care services utilization, including general practitioner (GP) home visits, GP 101 clinic visits and GP telephone contacts. For most of these outcomes, there were no statistically significant differences between the BUD/FM and FP/SM groups. The systematic review and three of the four trials were relatively consistent in finding no difference between groups. One trial reported fewer symptoms, nocturnal awakenings, exacerbations, hospitalization days, and unscheduled 101 outpatient visits for those treated with FP/SM than for those treated with BUD+FM. This trial was the smallest (N = 428) and shortest in duration (12 weeks) among the four making this comparison. It was also the only one that administered BUD+FM in separate inhalers and used a two-fold greater dose of BUD than the other trials. The only other included outcomes that were statistically significantly different between 98, 99 treatments were from a 6-month trial. Specifically, the authors reported greater improvement in the number of rescue puffs used per day for those treated with FP/SM (mean difference, 95% CI: 0. The total number of hospitalizations or emergency visits was not analyzed for statistical significance, but there were fewer such events in the BUD/FM arm compared with the FP/SM arm (72 and 106, respectively). A post-hoc analysis of the original study that was limited to participants ages 16 and above yielded similar results. Of note, the total daily dose of BUD delivered by DPI in this study is considered medium and the total daily dose of FP delivered by pMDI is considered high. There were additional numerical trends for some outcomes that favored one intervention 95 over the other but for which statistical tests were not performed. One study reported 101 numerically fewer hospitalizations/ER visits in patients treated with BUD/FM; another reported the same number of ER contacts in both arms but more inpatient days and outpatient hospital visits in the BUD/FM arm than in the FP/SM arm. It is unclear in the latter study how many hospital visits contributed to the total number of inpatient days.

Suppose safe 100mg kamagra chewable, for example generic 100mg kamagra chewable amex, that a parasite has two distinct antigenic sites. A parasite with genotype A/B at the two sites sweeps through the popula- tion, infecting all hosts. One-half ofthe host population maintains mem- ory against both antigens, one-quarter has immunodominant memory against A only, and one-quarter has immunodominant memory against B only. Now consider how this distribution of memory proﬁles inﬂuences the success of antigenic variants. A mutation at a single site, for example B,yieldsanaltered parasite, A/B. Thism utant can attack the quar- ter of the host population with memory only against B. Asthepara- site spreads, a second mutation to A /B allows attack of the remaining hosts. This example shows that strongly immunodominant host proﬁles lim- ited to one or a few sites allow parasite mutants with few changes to succeed. Once the variant parasite begins to spread between suscepti- ble hosts, additional mutations allow attack against hosts with diﬀerent immunodominant proﬁles or against hosts that developed broader im- munity against multiple antigenic sites. Inﬂuenza evolution may proceed by this sort of sequential accumula- tion of variation, with new epidemic strains diﬀering from the previous epidemic strain at several sites (Natali et al. Surveys of human popula- tions and laboratory studies of mice and rabbits support this hypoth- esis by showing that individuals often have narrowly focused antibody 134 CHAPTER 9 responses and that individuals vary in the antigenic sites to which they develop antibodies. In the laboratory, studies show that individual mice infected with hu- man inﬂuenza often produce antibody responses focused on a limited number of antigenic sites—probably just one or two sites (Staudt and Gerhard 1983; Underwood 1984; Thomas et al. Individual mice diﬀered in the antigenic sites to which they raised antibodies. Individ- ual variation in antibody response probably occurs because stochastic recombinational and mutational processes generate antibody speciﬁcity (Staudt and Gerhard 1983). Surveys of human populations ﬁnd that individuals previously ex- posed to inﬂuenza vary in antibody memory proﬁles (Natali et al. For samples collected from the early years of the Hong Kong inﬂuenza subtype epi- demics (1969 and 1971), 33% of individuals had antibodies to all three sites, 50% had antibodies for two sites, and 17% hadantibodies for only one site. Approximately equal numbers of individuals lacked antibody to any particular site, suggesting that each site was equally likely to stim- ulate an antibody response. Most individuals sampled in 1978 had anti- bodies for all three sites. It appears that after several years of repeated exposure to various strains of the Hong Kong subtype, individuals had acquired a wider repertoire of antibodies. Human children tend to have particularly narrowly focused antibody proﬁlesagainst inﬂuenza (Natali et al. This may occur either because of children’s relatively smaller number of exposures or because of their narrower response per infection. Theseobservations on mice and humans support the hypothesis that individuals have narrowly focused antibody memory and that individu- als vary in the antigenic sites to which they respond. This combination of individual focus and population variability creates a heterogeneous pat- tern of selection onparasites. After a widespread epidemic by a single parasite type, the parasite must acquire several new mutations before it can again spread widely through the population. Stepwise changes can occur by ﬁrst changing at one site and attacking a subset of the population with a dominant response against that site. The new mu- tant strain can then accumulate a second change that provides access IMMUNOLOGICAL VARIABILITY OF HOSTS 135 both to hosts with a dominant antibody response to the second mutant site and to hosts with antibodies against both the ﬁrst and second mu- tant sites. Additional mutations allow attack against broader sets of immunological proﬁles. This description certainly oversimpliﬁes the actual process. However, the immunodominance of individual hosts for particular epitopes and the population variability of immune proﬁles can create important se- lective pressures on parasites. Typically,memoryleads to a faster and more vigorous secondary response.

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